Ivabradine

Indications

Ivabradine is FDA-approved in the United States for use in patients with symptoms due to stable heart failure and an ejection fraction of 35% or less to reduce their risk of hospital admission for worsening heart failure.

Patients on ivabradine therapy should have a resting heart rate of at least 70 beats per minute and must be in normal sinus rhythm. They should also be on their maximum tolerated beta blocker or have a contraindication to beta-blocker use.

In Europe, ivabradine is indicated in the treatment of heart failure and chronic stable angina.

Mechanism of Action

Ivabradine blocks the channel responsible for the cardiac pacemaker current, I(f), which regulates heart rate. This results in prolonged diastolic time and reduced heart rate.

Rapid resting heart rate can lead to detrimental effects on left ventricular function and has been associated with negative outcomes in patients with cardiovascular disease. Reducing resting heart rate to reduce cardiovascular morbidity and mortality is, therefore, a therapeutic target among drug manufacturers. Ivabradine reduces heart rate but does not affect myocardial contraction, relaxation, or ventricular repolarization.

Administration

Ivabradine is available as tablets to be taken by mouth.

The initial dose should be 5 mg, twice a day.

The dose can be adjusted after 2 weeks based on the heart rate.

The maximum dose is 7.5 mg, twice a day.

Patients with conduction defects or bradycardia can be initiated on 2.5 mg, twice a day.

The reduction in heart rate depends on the baseline heart rate and the ivabradine dose.

Dose Adjustment

If heart rate is more than 60, increase the dose by 2.5 mg, twice a day, up to 7.5 mg twice a day.

If heart rate is 50-60 bpm, continue the current dose.

If heart rate is less than 50 or if the patient is experiencing symptoms of bradycardia, decrease the dose by 2.5 mg, twice a day. If the dose is 2.5 mg twice daily, stop therapy.

Clinical Evidence

The SHIFT trial was a double-blind, placebo-controlled study of patients with symptomatic heart failure, ejection fraction (EF) less than or equal to 35%, in sinus rhythm with a heart rate of at least 70 beats per minute, who had been admitted for heart failure within the past year and were on stable heart failure treatment including beta blockers. Patients received ivabradine titrated to 7.5 mg twice a day or placebo. The goal was to determine if ivabradine would decrease hospitalizations and/or mortality due to heart failure. Ivabradine reduced the primary endpoint which was a composite of hospital admissions due to heart failure and mortality. Bradycardia and visual adverse effects (phosphenes) occurred more in patients receiving ivabradine than in those in the placebo group.

The BEAUTIFUL trial was a randomized, placebo-controlled, multinational trial to test whether reducing heart rate with ivabradine affected cardiovascular morbidity and mortality in patients with coronary artery disease and EF less than 40%. Patients had a resting heart rate of at least 60 beats per minute. Patients received ivabradine 5 mg twice a day with a goal of 7.5 mg twice a day versus placebo. Most patients were also on beta-blocker therapy. Ivabradine did not affect the primary composite endpoint of cardiovascular mortality, hospital admissions for myocardial infarctions or worsening heart failure. In patients with heartbeats of 70 or greater, ivabradine reduced hospital admissions due to fatal or non-fatal myocardial infarction.

SIGNIFY was a randomized trial that tested the addition of ivabradine to standard therapy in patients with stable coronary artery disease but no heart failure. Patients had to be at least 55 years old with a heart rate of 70 beats or more. The goal heart rate was 55 to 60 beats per minute. Patients received 10 mg of ivabradine twice a day or placebo. The primary endpoint was a composite of death or nonfatal myocardial infarction. After 28 months, there was no significant difference between ivabradine and placebo. Bradycardia occurred more with ivabradine compared to placebo. The primary endpoint was higher in patients in the ivabradine group who initially had angina that limited activity.

Adverse Effects

The most common adverse effects include bradycardia, atrial fibrillation, high blood pressure, and phosphenes.

Ivabradine can cause bradycardia, sinus arrest, and heart block. Sinus node dysfunction, first- or second-degree atrioventricular block, bundle branch block, ventricular dyssynchrony, and or concomitant use of other heart-rate reducing drugs increase the risk of bradycardia. In the SHIFT trial, symptomatic bradycardia occurred in 5% of patients taking ivabradine compared to 1% in the placebo group. Asymptomatic bradycardia occurred in 6% of patients on ivabradine compared to 1% in the placebo group. Bradycardia led to permanent withdrawal from the study in 1% of patients on ivabradine and less than 1% of those in the placebo group.

Ivabradine is metabolized by CYP3A4. Concomitant use of verapamil or diltiazem with ivabradine should be avoided. Verapamil and diltiazem are CYP3A4 inhibitors; they increase ivabradine levels and hence the risk of bradycardia.

QT prolongation, torsade de pointes, and other arrhythmias may occur as a result of ivabradine-induced bradycardia.

Visual effects (phosphenes) were observed in clinical trials. It has been proposed that this is due to ivabradine's inhibition of I(h) current in the retina. In the SHIFT trial, known phosphenes occurred in 3% of patients taking the ivabradine compared to less than 1% in the placebo group. This difference in the occurrence of phosphenes was statistically significant.

Monitoring

Monitor cardiac rhythm

Monitor heart rate

Monitor for symptoms of bradycardia

Monitor pregnant women for preterm birth with chronic heart failure in the third trimester of pregnancy

Toxicity

Fetuses of pregnant rats had embryo-fetal toxicity and cardiac teratogenic effects when treated at exposures 1 to 3 times the human exposures at the maximum recommended human dose. No adequate studies of ivabradine in pregnant women provide information on the drug's possible risk to the mother or fetus. Contraception is recommended in female patients taking ivabradine.